1. Field of the Invention
The invention relates generally to compositions and methods for reducing or preventing allergies or their symptoms and specifically to compositions and methods for reducing or preventing allergies or their symptoms caused by environmental allergens.
2. Description of the Related Art
Allergy can be defined as a state of immune responsiveness in an animal to an exogenous antigen (or allergen) that is not otherwise harmful to the animal.
Environmental allergens include allergens that derive from organisms such as plants, molds, animals, and insects. Examples of environmental allergens include plant pollens, and mold spores. Other environmental allergens are found in the excretions of furred animals, and insects, such as mites and cockroaches.
Environmental allergens pose a health threat to people of all ages, most particularly children. The presence of such allergens in the environment can result in symptoms or responses that range from mild rhinitis, to skin problems (e.g., itching and hives), asthma, acute respiratory distress, and even to life-threatening anaphylactic reactions.
Certain environmental allergens, for example, the food allergens from tree nuts and especially peanuts have gained significant attention of the public because of coverage in the popular media. Notwithstanding the greater public awareness, as well as improved understanding of the pathophysiology of allergic responses in sensitized individuals, and improved therapies and treatment modalities, medical researchers have noted an increase of epidemic proportions in recent years in both morbidity and mortality for many of the symptoms and allergic responses noted above in both developing and developed nations. For example, asthma has reportedly increased over the past 2 decades in all age groups, particularly in inner city children. The reasons behind the noted increases are likely multifactorial, but include increased exposure to both indoor and outdoor environmental allergens, as well as improved awareness by both the public and the medical community with resultant increased diagnosis by medical practitioners.
Despite the widespread occurrence of many environmental allergens, major strategies that have been developed as methods for controlling the reactions to such allergens include establishing tolerance, and simple avoidance.
Avoidance strategies have been endorsed by the National Institutes of Health as significant in the treatment or prevention of allergy-induced health problems. Unfortunately, although removal of individuals to “allergen-free mountain institutions or hospitals” resulted in prolonged improvement of the environmental allergen-induced symptoms, it is not practical in many cases that such allergens can be completely avoided, or that allergic persons can afford the time and expense of such institutions. However, it is mildly encouraging that clinical studies show that avoidance of one allergen, even where others are not avoided can result in reduced symptoms, for example, of asthma. Thus, for example, environmental dust mite allergen avoidance successfully mitigated symptoms where mite populations were controlled and related allergen concentrations were lowered at least 100-fold.
Tolerance strategies entail establishment or reestablishment of a nonharmful or more productive response to exogenous allergens. Such an immune state is far more functional than the counter-productive, potentially fatal, over-response of the allergic immune system. Tolerance-inducing strategies have included allergen immunotherapy, wherein the sensitized animal is intentionally exposed to the allergen in a controlled manner, for example through a series of injections, or through oral or nasal absorption. Immunotherapy has been in use for over 100 years, and has been successful, although it may take years to establish an acceptable level of tolerance. A more recent strategy for establishing tolerance involves the use of allergen peptide-based approaches. In some applications, this has involved conjugated or chimeric molecules containing immunostimulatory sequences linked to the allergen. There has been work recently in the area of creating chimeric molecules comprising a portion of human immunoglobulin (IgG Fc) covalently linked to Fel D1. This molecule can essentially paralyze the allergic cell reactivity during treatment, while also inducing tolerance to the Fel D1 in the treated person. The chimeric molecule results in a complex coaggregation of mast cells with basophils the nature of which actively inhibits mediator release, thus minimizing any significant allergic response, even with immunotherapy-inducing doses of the allergen. Tolerance strategies have also employed cellular approaches designed to convert naïve CD4+ T-cell into regulatory T-cells that mitigate a tolerant response to an allergen.
Tolerance strategies, while potentially effective in the specific individual receiving the treatment, are expensive, invasive, time-consuming, and require experts such as doctors, immunologists, and the like, for administration. Treatments for tolerance also involve a certain level of risk associated with adverse reactions and negative outcomes. Further, other animals in the environment that are exposed to the allergen receive no benefit from the treatment—i.e., they are totally individualized. Thus avoidance strategies, where applicable may offer advantages.
Avoidance strategies may be most easily facilitated for allergens that have specific, identifiable point sources. In addition to dust mites, pet allergies are specifically traceable to the pet source. In the case of allergies to cats, although multiple allergens may be present, it has been determined that one specific allergen, Fel D1, is the source of a significant proportion of allergic response in sensitized individuals (Ohman J. L., Lowell F. C. and Bloch K. J. (1974) Allergens of mammalian origin. III. Properties of major feline allergen. J. Immunol. 113: 1668-77). The allergen Fel D1 is shed from the cat's sebaceous glands in the skin, and through cat saliva during grooming. It is a leading cause of cat allergies.
Thus, while cat ownership is on the rise in the United States, allergies to cats have become/remain the primary reason for relinquishment of cats to animal shelters (Scarlett et al., J. Appl. Animal Welfare Sci., 2 (1):41-57, 1999). A study of households with cats indicated that Fel D1 is widely present. The allergen was nearly ubiquitous in the house being identified in 96.6% of the beds, 96.9% of bedroom floors, 96.1% of living room floors, and 97.9% of sofas. (Geany et al., Pediatrics, 116 (2): August 2005). Clothing from school children from homes containing cats was tested of school tested outside of the home (in schools), and found to contain Fel D1 antigens. Thus, this environmental antigen poses a substantial risk, not only to sensitized individuals living in households with cats, but to the allergic human population on the whole. (Gerge & Dreborg, Ped. Allergy Immun., 9 (1):25-30, 1998).
Fel D1 allergens can be readily detected via in-home ELISA tests. About 14% of children 6 to 19 years of age or older are allergic to cats (NIH news release). Avoidance of Fel D1 could help with owner appeal, pet ownership, and health of children and sensitized pet owners.
Avoidance as a general concept, however, is difficult to embody by practical means. A reduction in the amount of Fel D1, even a minimal reduction, could have substantial impact on the health of sensitized individuals, and could minimize relinquishment as a result of a person in home becoming sensitized. To date, strategies for reducing Fel D1 have included physical isolation or removal, for example by keeping the allergic person in a clean space that is not occupied by the cat, or through regular bathing of the subject cat to minimize Fel D1 dispersal.
In another approach for physically removing Fel D1 from the environment, cats genetically modified so as to not produce Fel D1 are now available on the market. These engineered cats lack the gene to produce the allergenic form of Fel D1, and instead produce a different, non-allergenic protein. While this approach may prove effective, it remains relatively untested and nothing is publicly-known about the long-term health and vigor of the resultant cats. Further, the available types and selection of such genetically-altered cats is very limited. In addition, the animals are very expensive, ranging from about $3,000 to $5,000 ($U.S.).
To aid in considering strategies for addressing environmental allergen issue, it is instructive to have an understanding of allergic reactions in the immune system. The allergic response begins with sensitization that results in production of allergen specific IgE-antibodies. For example, when an allergen is inhaled, antigen presenting cells in the airway mucosa, internalize, and process the allergen. The allergens are then expressed on their cell surface and are then presented to other immune cells, particularly T-lymphocytes. As a result, B-lymphocytes are transformed into antibody secretory plasma cells. In an allergic response, the plasma cell produces IgE antibodies that have specific binding for a specific allergen. Once in circulation, IgE binds to high affinity receptors on mast cells, basophils, Langerhans cells, and activated monocytes. Such binding leaves the IgE's allergen-specific receptor site free for further interaction with the same allergen.
Upon re-exposure to the allergen, binding of the allergen to IgE initiates a rapid and intense response from the immune system. Cross-linking of mast cell/basophil-bound IgE antibodies by allergen begins an intra-cellular signaling cascade, which causes degranulation of immune cells, and concomitant release of inflammation mediators. Mast cells regulate their IgE receptor expression to keep the number of unoccupied IgE receptor sites constant. Circulating IgE antibodies bind to these receptor sites, waiting for their specific allergen to be encountered.
The immune system's response to allergen exposure can be divided into immediate hypersensitivity or early phase reaction, that occurs within 15 minutes of exposure to the allergen, and a second, or late phase reaction that occurs 4-6 hours after the disappearance of the first phase symptoms and can last for days or even weeks. The early phase is characterized by mediators released by mast cells including histamine, prostaglandins, leukotrienes, and thromboxane. These generate responses characteristic of an allergies in tissue local to the IgE and mast cells. Sneezing, swelling and congestion, nasal blockage, bronchoconstriction, coughing and wheezing are well-known effects. The late phase reaction can be characterized by cellular infiltration, fibrin deposition and tissue destruction in the lung, leading to increased bronchial reactivity, oedema and inflammation. Thus, the interaction of allergen, IgE, and mast cells is central to the immune system's response and results in the triggering of mast cell mediator release, leading directly to both the early and late phase reactions.
WO07113633A2 discloses methods for reducing the amount of Fel D1 shed by a cat by administering to a cat an immunogenic composition comprising at least one Fel D1 polypeptide or its fragment or a polynucleotide molecule encoding Fel D1 polypeptide. US2006000474180 discloses fusion proteins comprising an allergen sequence such as those for Fel D1 linked via an IgG hinge region to another polypeptide sequence capable of specifically binding to a native IgG inhibitory receptor containing an immune receptor tyrosine based inhibitory motif (ITIM). WO06097530A2 discloses medicaments for treating cat allergy comprising a virus-like or virus core particle, with first attachment site, and specific feline protein antigen, with second attachment site, covalently linked via the sites.
Recent advances in methods of antibody production may allow alternative means for avoiding environmental antigens that cause allergy in sensitized individuals. For example, milk-based antibody systems and egg based antibody systems, e.g., US20030003133A1 discloses using milk as a carrier for allergens for inducing oral tolerance to cat dander and other allergens.
Thus, there is a need in the art for compositions and methods useful for reducing environmental allergens and thereby reducing, minimizing or even preventing an allergic response, or symptoms of such a response, in an animal predisposed to having such a response when exposed to the allergen.